LSD1 is a demethylation enzyme of histone, catalyzes a demethylation reaction of a monomethylated product and a demethylated product of the 4th lysine residue of histone H3 (H3K4mel/2), and forms formaldehyde as a by-product. In addition, LSD1 forms a complex with flavin adenine dinucleotide (FAD) which is a kind of coenzyme, and FAD promotes oxidation of lysine residue by enzymes as a redox mediator.
When a compound having an LSD1 inhibitory activity is allowed to act on a nerve cell, H3K4 methylation, from the methylation modifications of histone H3 (GAD1 gene promoter), is particularly promoted due to the inhibition of LSD1 histone demethylation enzyme activity by the compound (Experimental Example 3 to be mentioned later). There are many reports on the analyses of gene expression level and histone H3K4 methylation state, which conclude that promotion of histone H3K4 methylation at a gene promoter leads to an activated transcription of the gene (Becker et al., Nature 2006, 442: 31-32; Ruthenburg et al., Nature Reviews Molecular Cell Biology 2007, 8: 983-994). Therefore, it is assumed that administration of a compound having an LSD1 inhibitory activity accumulates histone H3K4 methylation in neurons in the brain, which in turn results in the GAD1 mRNA expression in the brain. It is widely known that the induction of GAD1 mRNA expression in the brain is effective for the treatment of central nervous system diseases. For example, intracerebral injection of a GAD1 gene expression vector to Parkinson's disease patients is known to induce GAD1 mRNA expression and improve the symptoms of Parkinson's disease patients (Lewitt et al. Lancet Neurol. 2011, 10: 309-319; Carlson Physiology of Behavior 11th edition 2013). From the above, it is considered that the administration of an LSD1 inhibitor increases the histone H3K4 methylation to increase the GAD1 expression level in the brain, which may be effective for the treatment of central nervous system diseases.
WO 2010/084160 (patent document 1) discloses a compound of the following formula or a pharmaceutically acceptable salt thereof as an LSD1 inhibitor:
wherein R1-R5 are H, halo and the like; R6 is H or alkyl; R7 is H, alkyl or cycloalkyl; R8 is -L-heterocyclyl or -L-aryl wherein L is —(CH2)n—(CH2)n—, —(CH2)nO(CH2)n— or —(CH2)nS(CH2)n—, and n is 0, 1, 2 or 3.
WO 2010/043721 (patent document 2) discloses a compound of the following formula or a pharmaceutically acceptable salt thereof as an LSD1 inhibitor:
wherein R1-R5 are H, halo and the like; R6 is H or alkyl; R7 is H, alkyl or cycloalkyl; R8 is —C(═O)NRxRy or —C(═O)Rz wherein Rx and Ry are each independently H, alkyl and the like, and Rz is H, alkoxy and the like.
WO 2011/035941 (patent document 3) discloses a compound of the following formula or a pharmaceutically acceptable salt thereof as an LSD1 inhibitor:(A′)x-(A)-(B)-(Z)-(L)-(D)  Iwherein (A′) is aryl, arylalkoxy, heterocyclyl and the like; (A) is heteroaryl or aryl; X is 0, 1, 2 or 3; (B) is a cyclopropyl ring; (Z) is —NH—; (L) is —CH2CH2— and the like; (D) is —N(—R1)-R2, —O—R3 or —S—R3 wherein R1 and R2 are each independently H, alkyl and the like; and R3 is H, alkyl and the like.
WO 2011/042217 (patent document 4) discloses a compound of the following formula or a pharmaceutically acceptable salt thereof as an LSD1 inhibitor:(A′)x-(A)-(B)-(Z)-(L)-C(═O)NH2  (I)wherein (A′) is aryl, arylalkoxy, arylalkyl, heterocyclyl and the like; (A) is heteroaryl or aryl; X is 0, 1, 2 or 3; (B) is a cyclopropyl ring; (Z) is —NH—; (L) is —(CH2)mCR1R2- wherein m is 0, 1, 2, 3, 4, 5 or 6; and R1 and R2 are each independently H or C1-6 alkyl.
US2010/0324147 (patent document 5) discloses a compound of the following formula or a salt thereof as an LSD1 inhibitor:
wherein X is a bond, O, S or NH; and RA, RB, RC, RD, and RE are each independently H, C1-7 alkyl and the like.
WO 2010/143582 (patent document 6) discloses a compound of the following formula or a pharmaceutically acceptable salt thereof as an LSD1 inhibitor:
wherein R1 is H, an alkyl group optionally having a substituent attached thereto and the like; R2 is an alkylene group optionally having a substituent attached thereto; R3 is an alkyl group optionally having a substituent attached thereto, a phenyl group optionally having a substituent attached thereto and the like; R4 is an alkyl group optionally having a substituent attached thereto, a phenyl group optionally having a substituent attached thereto and the like; and X is O, NH2, NHCO, CONH, S or CH2.
J. Am. Chem. Soc. 2010, 132, 6827-6833 (non-patent document 1) discloses compounds of the following formulas as an LSD 1/2 inhibitor:

WO2012/156531 (patent document 7) discloses use of an LSD1 inhibitor for the prophylaxis or treatment of inflammatory diseases.
WO2012/156537 (patent document 8) discloses use of an LSD1 inhibitor for the prophylaxis or treatment of thrombosis, thrombus formation or circulatory diseases.
WO2012/135113 (patent document 9) discloses, as an LSD1 inhibitor, a compound of the following formula or a pharmaceutically acceptable salt thereof:
wherein    R1 is selected from the group consisting of C1-6 alkyl, —NSO2Me, —NSO2Ph, arylalkoxy, C3-7 cycloalkyl, —NC(O)Ra, 1-methyl-1H-pyrazol-4-yl, hydroxy, C1-4 alkoxy, halogen, amide, amino, substituted amino and —C(O)ORa;    R2 is H or COOH;    each R3 is independently selected from the group consisting of aryl, heteroaryl, H, C1-6 alkyl, —SO2Ra, —NC(O) Ra, —CH2C(O)ORa, —C(O)ORa, —C(O)Ra, —C(O)NRaRb, substituted amino, amino, urea, amide, sulfonamide, arylalkyl and heteroarylalkyl;    each Ra is independently H, phenyl, phenylmethyl, 3,5-dimethylisoxazol-4-yl, 1,2-dimethyl-1H-imidazol-4-yl, C3-7 cycloalkyl, C1-6 alkyl, C1-4 alkoxy, C1-3 alkylamino or —NHPh;    Rb is H or C1-3 alkyl, or when attached to the same atom, Ra and Rb together form a 5- or 6-membered heterocycloalkyl ring;    R4 is C1-4 alkyl, acyl, —C(O)CF3 or H;    W is —(CH2)1-4 or —CH(Rc) (CH2)0-3 wherein Rc is CN or C1-4 alkyl;    Y is N or C;    X is N or C;    Z is O or (CH2)q wherein q is 0-2, and when q is 0, Z is a bond;    m is 0-3, n is 0-3;    provided that when Z is O, Y is N and X is C;    also provided that when X is C, at least one of the R3 groups attached to X is not H.
The Journal of Neuroscience, Oct. 17, 2007, 27(42): 11254-11262 (non-patent document 2) discloses that a decrease in histone H3K4 methylation and a decrease in Gad1 mRNA expression are observed in the brain of schizophrenia patients.
MOLECULAR AND CELLULAR BIOLOGY, August 2011, 31(16), 3298-3311 (non-patent document 3) discloses that LSD1 contained in a protein complex that regulates transcription of beta globin may be involved in the suppression of transcription of beta globin. Activation of beta globin transcription is known to be useful for the treatment of sickle cell anaemia and beta thalassemia, from which it is assumed that LSD1 inhibition disinhibits beta globin transcription, and provides a treatment effect.